perspec tives
nature publishing group
commentaries Dosing Tacrolimus Based on CYP3A5 Genotype: Will It Improve Clinical Outcome? T van Gelder1,2 and DA Hesselink2 Tacrolimus, widely used to prevent acute rejection following solid-organ transplantation, has become the cornerstone of immunosuppressive therapy after kidney transplantation. More than 70% of all renal transplant recipients receive this remarkably effective agent.1 But tacrolimus is also highly toxic, and there is great between-patient variability in its pharmacokinetics. This, combined with a low therapeutic index, mandates routine therapeutic drug monitoring in clinical practice.2 Typically, predose concentrations are monitored and the dose is adjusted to aim for target values that depend on immunological risk, comedication, and time since transplantation.2
Several investigators have shown that single-nucleotide polymorphisms (SNPs) in the CYP3A5 gene explain part of the between-patient variability in the pharmacokinetics of tacrolimus. A SNP at position 6986 of the CYP3A5 gene (6986A>G) causes a splicing defect, resulting in absence of functional CYP3A5 protein. Patients homozygous for the 6986G-allele (designated as CYP3A5*3) have no CYP3A5 activity. Carriers of at least one 6986A-allele (CYP3A5*1 carriers) do have functional CYP3A5 and require a higher dose of tacrolimus to reach the targeted whole-blood concentrations.3 MacPhee et al. also showed that in the first 2 weeks after transplantation, CYP3A5 expressers experience a delay in reaching target concentrations.4 The underexposure to
tacrolimus in the first weeks could put these patients at increased risk for acute rejection. With this in mind, it would make sense to individualize the starting dose of tacrolimus dose according to a patient’s CYP3A5 genotype. In this issue, Thervet et al. report the results of a randomized controlled trial that compared the efficacy of tacrolimus dosing based on an individual’s CYP3A5 genotype to a standard tacrolimus dosing regimen based on body weight.5 A total of 280 recipients of a deceased-donor kidney transplant were randomized. All patients received induction therapy with either antithymocyte globulin (ATG) (82% of patients) for 5 days or treatment with monoclonal antibodies against the interleukin-2 receptor (18% of patients).
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In addition, all patients received 3 g daily of mycophenolate mofetil (MMF) plus glucocorticoids. Twice daily tacrolimus treatment was not started until day 7 after transplantation, and the first measurement of the tacrolimus predose concentration was performed after the intake of six doses. Three days after initiation of tacrolimus treatment, more patients were within the target window when their tacrolimus dose was individualized based on their CYP3A5 genotype as compared with patients receiving a standard tacrolimus dose (43.2% vs. 29.1%, respectively; P = 0.03). In addition, patients receiving the CYP3A5 genotype–based tacrolimus dose reached their target concentrations more rapidly and required significantly fewer dose modifications. Clinical outcome, including the incidence of acute rejection and delayed graft function, did not differ significantly between the two groups. This proof-of-concept study demonstrates for the first time that it is indeed possible to improve tacrolimus dosing by using a strategy that takes an individual’s CYP3A5 genotype into account. However, the study population consisted of patients at low immunological risk for acute rejection, and the large majority of the patients received ATG induction therapy together with a high dose of MMF. Therefore, the investigators were able to delay the introduction of tacrolimus for a week (allowing them to perform CYP3A5 genotyping). It is thus not surprising that there were no important differences in clinical outcome despite the fact that tacrolimus concentrations were not on target immediately. This is acknowledged by the authors, who suggest that similar studies in high-risk patients, or in a setting without induction therapy, are needed to evaluate the true clinical relevance of CYP3A5
1Department of Hospital Pharmacy, Erasmus Medical Center, Rotterdam, The Netherlands; 2Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. Correspondence: T van Gelder (
[email protected])
doi:10.1038/clpt.2010.42 640
VOLUME 87 NUMBER 6 | JUNE 2010 | www.nature.com/cpt
perspec tives genotype-based tacrolimus dosing. In addition, a beneficial effect of CYP3A5based dosing on the incidence of delayed graft function may become apparent only if treatment with tacrolimus is started on the day of transplantation. Given the extensive use of therapeutic drug monitoring in transplanted patients, one could argue that the contribution of genotype-based tacrolimus dosing will remain limited. In the early phase after transplantation, tacrolimus levels are monitored multiple times each week; with adequate dose adjustments, almost all patients will reach levels above the lower limit of the target window within 1 or 2 weeks. In a recent prospective study, we showed that patients carrying at least one CYP3A5*1 allele (CYP3A5 expressers) had significantly lower predose concentrations 3 days after the initiation of tacrolimus treatment; at day 10, however, this difference had already disappeared.6 Reaching target concentrations by implementing genotype-based dosing can be viewed only as a surrogate end point. A reduced incidence of acute rejection would be considered a more convincing argument to make the transition to a pharmacogenetic approach. Moreover, physicians have a resistance to relying on tests for every medical decision, and a “trial and error” approach to drug dosing (including that of tacrolimus) has become widely accepted.7 Successful incorporation of a pharmacogenetic test into clinical practice would be more likely to occur for drugs for which the pharmacokinetics are not routinely monitored and outcome is closely linked to genotype. An example is abacavir, the nucleoside reverse-transcriptase inhibitor with activity against HIV. The potentially fatal, immunologically mediated hypersensitivity reaction to abacavir, observed in about 5% of patients, is not associated with increased drug exposure. Several investigators have found a strong association between this hypersensitivity reaction and the presence of the HLA-B*5701 allele. In a prospective randomized trial, it was shown that exclusion of HLAB*5701-positive patients from abacavir treatment reduced the incidence of the hypersensitivity.8 Following the publication of this trial, registration authorities in many countries now require physicians
to test for the HLA-B*5701 allele before prescribing abacavir. Likewise, CYP3A5 genotyping may also have a future in the prediction of tacrolimus-related adverse events. One of the most dreaded complications of prolonged treatment with the calcineurin inhibitors tacrolimus and cyclosporine is their nephrotoxicity; it is accompanied by extensive alterations of the renal architecture, which is generally irreversible.9 Tacrolimus concentrations in renal tubular cells are not correlated 1:1 with whole-blood concentrations, and systemic exposure to tacrolimus is a poor predictor of chronic tacrolimusinduced nephrotoxicity. This may be due to the presence of drug-transporting enzymes in the cell membranes of renal tubular cells or to CYP3A5 activity within the kidney. One of these transporters is ABCB1 (formerly known as P-glycoprotein), which functions as an efflux pump for drugs that enter the cell. Genetic polymorphisms in the ABCB1 gene may result in differences in the accumulation of tacrolimus intracellularly, and polymorphic expression of CYP3A5 (which is the main CYP3A isoform in the kidney) may lead to variability in the intrarenal concentrations of tacrolimus metabolite. Given that the ABCB1 and CYP3A5 activities involved in the intrarenal disposition of tacrolimus are not of recipient origin, the genotype of the donor should be taken into account in studies investigating the pharmacogenetics of tacrolimus-induced nephrotoxicity. The first studies showing the relevance of this assumption have already been published. Naesens et al. showed that the ABCB1 genotype and expression of ABCB1 in renal tubular epithelial cells of the kidney transplant determine susceptibility of transplanted kidneys to chronic tubulointerstitial damage.10 Although it is still too early to base clinical decisions on these findings, they do indicate that it may become possible to select patients perceived to be at high risk of tacrolimusrelated toxicity for treatment with immunosuppressive regimens free of calcineurin inhibitor or for the early withdrawal of these agents. Polymorphisms in genes encoding for proteins involved in the transport of drugs over the cell membrane are more likely to be of use compared with polymorphisms in genes encoding for pro-
Clinical pharmacology & Therapeutics | VOLUME 87 NUMBER 6 | JUNE 2010
teins involved in drug metabolism, as the influence of the latter can be minimized by monitoring drug concentrations in whole blood or plasma. We have reached the stage where technological advances have reduced the cost of reliable tests for genotyping sooner than science and medicine have been able to incorporate these pharmacogenetic tests into clinical practice.7 The “trial and error” approach has not yet evolved into individualized therapy benefiting from genetic tests. Prospective randomized trials such as the one by Thervet et al.5 can provide us with the high-level evidence we need to narrow the gap between scientific knowledge and clinical application. CONFLICT OF INTEREST T.v.G. has received consulting fees and grant support from F. Hoffmann–La Roche. D.A.H. has received lecture fees from Astellas Pharma. © 2010 ASCPT
1. Meier-Kriesche, H.U. et al. Immunosuppression: evolution in practice and trends, 1994–2004. Am. J. Transplant. 6, 1111–1131 (2006). 2. Wallemacq, P. et al. Opportunities to optimize tacrolimus therapy in solid organ transplantation: report of the European consensus conference. Ther. Drug. Monit. 31, 139–152 (2009). 3. Hesselink, D.A. et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin. Pharmacol. Ther. 74, 245–254 (2003). 4. MacPhee, I.A. et al. The influence of pharmacogenetics on the time to achieve target tacrolimus concentrations after kidney transplantation. Am. J. Transplant. 4, 914–919 (2004). 5. Thervet, E. et al. Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin. Pharmacol. Ther. 87, 721–726 (2010). 6. Hesselink, D.A. et al. CYP3A5 genotype is not associated with a higher risk of acute rejection in tacrolimus-treated renal transplant recipients. Pharmacogenet. Genomics. 18, 339–348 (2008). 7. Evans, W.E. & Relling, M.V. Moving towards individualized medicine with pharmacogenomics. Nature. 429, 464–468 (2004). 8. Mallal, S. et al. HLA-B*5701 screening for hypersensitivity to abacavir. N. Engl. J. Med. 358, 568–579 (2008). 9. Nankivell, B.J., Borrows, R.J., Fung, C.L., O’Connell, P.J., Chapman, J.R. & Allen, R.D. Calcineurin inhibitor nephrotoxicity: longitudinal assessment by protocol histology. Transplantation. 78, 557–565 (2004). 10. Naesens, M., Lerut, E., de Jonge, H., Van Damme, B., Vanrenterghem, Y. & Kuypers, DR. Donor age and renal P-glycoprotein expression associate with chronic histological damage in renal allografts. J. Am. Soc. Nephrol. 20, 2468–2480 (2009). 641
